This revised proposal is an R21 application for the ORWH Funding Opportunity Announcement Advancing Novel Science in Women's Health Research (ANSWHR) (PAS-10-226). Major depressive disorder (MDD) is prevalent in women of reproductive age, and the course of MDD across infertility treatment and implications for clinical management have not previously received systematic study. At this time, clinicians do not have evidence-based treatment guidelines on which to rely in order to advise women with histories of MDD who plan in vitro fertilization (IVF) or other assisted reproductive procedures. The context of infertility treatment is an intriguing and clinically compelling setting for the stuy of the biological stress response, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and risk for major depression. The aims of the study are: 1) to delineate the clinical predictors of depressive relapse in women with histories of depression across a period of six months while they are undergoing IVF including: antidepressant continuation or discontinuation, previous course of depressive illness, duration of attempt to conceive, and partner support, 2) to describe the trajectory of depressive symptoms over the course of IVF cycles, and 3) to explore biological markers of the stress response, including those pertaining to HPA axis dysregulation and inflammation associated with depressive relapse and stress during IVF treatment. We will conduct a prospective naturalistic investigation in which participants (N=60) will each be followed longitudinally for six months, during which time they will proceed through at least one IVF cycle. Mood symptoms, antidepressant use, psychotherapy, perceived stress, partner support, use of gonadotropins and any hormonal interventions, and all infertility based treatments and interventions across each cycle will be tracked prospectively. The significance of the proposal is derived from: 1) its public health implications in light of the high prevalence rats of both infertility and major depression in women, 2) the lack of systematic data regarding risk of depressive relapse and predictors of relapse in women undergoing IVF, and 3) the need for systematic study of the biological sequelae of stress among women with histories of depression undergoing treatment for infertility. PUBLIC HEALTH RELEVANCE: This revised proposal is an R21 application for the ORWH Funding Opportunity Announcement Advancing Novel Science in Women's Health Research (ANSWHR) (PAS-10-226). We will study risk factors for depressive relapse in women undergoing in vitro fertilization (IVF) with histories of major depression. These data will be used to develop larger studies in which the relationships between major depressive disorder, antidepressant use, and outcomes following infertility treatment are assessed prospectively.